Epigenetic predictive biomarkers for response or outcome to platinum-based chemotherapy in non-small cell lung cancer, current state-of-art

Szejniuk, Weronika Maria; Robles, Ana I.; McCulloch, Tine; Falkmer, Sture; Røe, Oluf Dimitri

doi:10.1038/s41397-018-0029-1

Cited by 39 publications

(30 citation statements)

References 73 publications

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“…Thus, it may not be surprising that MIR21 was the most responsive methylation locus to chemotherapeutic drugs. In recent years, there is a growing interest in the mechanistic, biomarker, and therapeutic roles of epigenetic pathways in response to chemotherapy [17,21,22]. The convergence of DNA methylation and microRNA as two potential epigenetic mechanisms on the same VMP1/MIR21 region in response to Fig.…”

Section: Discussionmentioning

confidence: 99%

Impact of chemotherapy for breast cancer on leukocyte DNA methylation landscape and cognitive function: a prospective study

Yao

Kerns

et al. 2019

Clin Epigenet

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Background: Little is known about the effects of chemotherapeutic drugs on DNA methylation status of leukocytes, which may be predictive of treatment benefits and toxicities. Based on a prospective national study, we characterize the changes in leukocyte DNA methylome from pre-to post-chemotherapy (approximately 4 months apart) in 93 patients treated for early stage breast cancer and 48 matched non-cancer controls. We further examined significant methylation changes with perceived cognitive impairment, a clinically significant problem related to cancer and chemotherapy. Results: Approximately 4.2% of the CpG sites measured using the Illumina 450K methylation array underwent significant changes after chemotherapy (p < 1e-7), in comparison to a stable DNA methylome in controls. Postchemotherapy, the estimated relative proportions of B cells and CD4 + T cells were decreased by a median of 100% and 39%, respectively, whereas the proportion of monocytes was increased by a median of 91%. After controlling for leukocyte composition, 568 CpGs from 460 genes were still significantly altered following chemotherapy. With additional adjustment for chemotherapy regimen, cumulative infusions, growth factors, and steroids, changes in four CpGs remained significant, including cg16936953 in VMP1/MIR21, cg01252023 in CORO1B, cg11859398 in SDK1, and cg19956914 in SUMF2. The most significant CpG, cg16936953, was also associated with cognitive decline in breast cancer patients. Conclusions: Chemotherapy profoundly alters the composition and DNA methylation landscape of leukocytes in breast cancer patients. Our results shed light on the epigenetic response of circulating immune cell populations to cytotoxic chemotherapeutic drugs and provide possible epigenetic links to the degeneration of cognitive function associated with chemotherapy.

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Section: Discussionmentioning

confidence: 99%

Impact of chemotherapy for breast cancer on leukocyte DNA methylation landscape and cognitive function: a prospective study

Yao

Kerns

et al. 2019

Clin Epigenet

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“…In particular, the inhibition of tumor suppressor expression by promoter hypermethylation is a common event in NSCLC [10]. Thus, DNA methylation-based biomarkers have been extensively studied for predicting prognosis and response to conventional therapy [11,12]. Silenced immune-related genes by promoter hypermethylation have been recently found to be predictive of ICB therapy response [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Genome-wide methylation patterns predict clinical benefit of immunotherapy in lung cancer

2020

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Background: It is crucial to unravel molecular determinants of responses to immune checkpoint blockade (ICB) therapy because only a small subset of advanced non-small cell lung cancer (NSCLC) patients responds to ICB therapy. Previous studies were concentrated on genomic and transcriptomic markers (e.g., mutation burden and immune gene expression). However, these markers are not sufficient to accurately predict a response to ICB therapy. Results: Here, we analyzed DNA methylomes of 141 advanced NSCLC samples subjected to ICB therapy (i.e., antiprogrammed death-1) from two independent cohorts (60 and 81 patients from our and IDIBELL cohorts). Integrative analysis of patients with matched transcriptome data in our cohort (n = 28) at pathway level revealed significant overlaps between promoter hypermethylation and transcriptional repression in nonresponders relative to responders. Fifteen immune-related pathways, including interferon signaling, were identified to be enriched for both hypermethylation and repression. We built a reliable prognostic risk model based on eight genes using LASSO model and successfully validated the model in independent cohorts. Furthermore, we found 30 survival-associated molecular interaction networks, in which two or three hypermethylated genes showed significant mutual exclusion across nonresponders. Conclusions: Our study demonstrates that methylation patterns can provide insight into molecular determinants underlying the clinical benefit of ICB therapy.

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“…More than four-fths of all lung cancers are characterized as non-small cell lung cancer (NSCLC), which is the most common subtype. Unfortunately, NSCLC is often diagnosed in advanced stages of the trait 1,2 . As such, further studies are needed to improve our understanding of NSCLC in order to identify new therapeutic targets and diagnostic biomarkers.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of circ-YES1 Suppresses NSCLC Migration and Proliferation Through The miR-142-3p–HMGB1 Axis

Chi

Wang

Zhou³

et al. 2020

Preprint

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Background: Circular RNAs (circRNAs) are a new family of abundant regulatory RNAs with roles in various types of cancer. While the hsa_circ_0046701 (circ-YES1) function in non-small cell lung cancer (NSCLC) is unclear. Methods: Circ-YES1 expression in normal pulmonary epithelial and NSCLC cells was examined. The small interfering RNA for circ-YES1 was prepared, cell proliferation and migration were assessed. Tumorigenesis in nude mice was assayed to validate the role of circ-YES1. Bioinformatics analyses and luciferase reporter assays were utilized to identify downstream targets of circ-YES1. Results: Compared to normal pulmonary epithelial cells, the circ-YES1 expression increased in NSCLC cells, and cell proliferation and migration were suppressed after circ-YES1 knockdown. Both high mobility group protein B1 (HMGB1) and miR-142-3p were found to be downstream targets of circ-YES1, and miR-142-3p inhibition and HMGB1 overexpression reversed the effects of circ-YES1 knockdown on cell proliferation and migration. Similarly, HMGB1 overexpression reversed the miR-142-3p overexpression effects on these two processes. The imaging experiment results revealed that circ-YES1 knockdown impeded tumor development and metastasis in a nude mouse xenograft model. Conclusion: Taken together, our results show that circ-YES1 promotes tumor development through the miR-142-3p–HMGB1 axis and support the development of circ-YES1 as a new therapeutic NSCLC target.

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Epigenetic predictive biomarkers for response or outcome to platinum-based chemotherapy in non-small cell lung cancer, current state-of-art

Cited by 39 publications

References 73 publications

Impact of chemotherapy for breast cancer on leukocyte DNA methylation landscape and cognitive function: a prospective study

Impact of chemotherapy for breast cancer on leukocyte DNA methylation landscape and cognitive function: a prospective study

Genome-wide methylation patterns predict clinical benefit of immunotherapy in lung cancer

Downregulation of circ-YES1 Suppresses NSCLC Migration and Proliferation Through The miR-142-3p–HMGB1 Axis

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